Abstract: The composition and function of the human intestinal microbiota is tightly linked to diverse aspects of host biology. Several diseases, including obesity and inflammatory bowel diseases, have been associated with altered microbiota composition. While much research is currently aimed at a genomic definition of the microbiota in both healthy and diseased states, there is a paucity of studies aimed at understanding this community at a mechanistic and ecological level, and how changes in its function and composition directly impact host biology. The question of whether disease-associated alterations in microbiota composition are a cause or symptom of disease is difficult to address due to the current lack of tools that allow us to test the effect of perturbations in microbiota structure and function on the host in a controlled experimental setting. And once we are able to identify a pathologic microbiota definitively, how will we return it to a healthy state? The goal of this research proposal is to identify small molecules that can alter the microbiota at the level of function and composition, providing (i) tools to aid investigation of altered microbiotas in model organisms and (ii) a model pipeline for identifying a new class of therapeutics that targets the intestinal microbiota. The ability to monitor host responses in gnotobiotic mice colonized with a normal human gut microbiota provides an unprecedented capacity to search for compounds that will be useful in human medicine. While others have speculated on the promise of targeting the microbiota to manipulate human health, specific plans of how this would be achieved are lacking. This proposal lays out a plan to screen for compounds that target specific taxa of the microbiota, characterize the targeted microbiota in vivo, and determine the impact on host biology. Public Health Relevance: A dense and complex community of microbes resides within each person's gastrointestinal tract and plays many important roles in our health, including aiding in our absorption of energy and nutrients from the foods we eat. In rare instances, members of this community can promote diseases, such as inflammatory bowel diseases (e.g. Crohn's disease or ulcerative colitis), demonstrating the precarious nature of our relationship with some of our microscopic associates. The goal of this research project is to identify small molecules that can be used as therapeutic agents to intentionally alter the composition and function of disease-associated gut microbes and thereby improve human health.